Panel Backs Approval of Second Biologic for Ulcerative Colitis

SILVER SPRING, MD. – The approval of a second anti-tumor necrosis factor treatment option for ulcerative colitis is likely, now that the majority of a Food and Drug Administration advisory panel has recommended approval of adalimumab for treating people with moderately to severely active disease.

At a meeting on Aug. 28, the FDA’s Gastrointestinal Drugs Advisory Committee voted 15-2 that the expected benefits of adalimumab – a subcutaneously administered tumor necrosis factor (TNF) blocker – outweighed its potential risks as a treatment for patients with moderately to severely active ulcerative colitis (UC) who have not had an adequate response with conventional treatments. The panel’s recommendation for approval was based on the results of two studies comparing adalimumab against placebo in such patients. But their support for approval came with caveats. While most of the panel agreed that the dose used in the studies had been shown to be clinically effective, they agreed that the optimal dose for treating UC had not yet been determined and that post-approval studies were needed to address dosing, subpopulations of patients who may benefit most from treatment, and long-term safety.

Panel members voting in favor of approval cited the need for more treatments and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects. And although the differences in clinical remission rates between placebo and treatment at 8 weeks and at 1 year were less than 10% – one of the main issues raised by FDA reviewers – most of the panel members said that these differences still represented a clinically meaningful benefit. Infliximab (Remicade), an intravenous TNF blocker, is approved for treating UC and Crohn’s disease in pediatric and adult patients.

Like other panelists, Dr. Andelka LoSavio of the department of gastroenterology and nutrition, Loyola University, Maywood, Ill., said that the outstanding issues should not hold up approval of adalimumab for UC. "Once the drug is on the marketplace, we will have more insight into subpopulations where the drug may be more effective," which was the case with Crohn’s disease and adalimumab.

Although the remission rates in the studies were low, these are difficult-to-treat patients, and the responses were statistically significant, with evidence of a steroid-sparing effect, said panelist Dr. Marc Wishingrad, a gastroenterologist who practices in Santa Monica, Calif. "So it seems to me in a global sense that there is enough benefit here, that overall I would recommend that this drug be approved for this indication," he added.

Panelists supported the manufacturer’s recommendation that if a patient does not respond after 8 weeks of treatment, that treatment should be stopped.

The two statisticians on the panel did not support approval, voting no on the risk-benefit question for reasons that included the modest effects on clinical remission rates, uncertain durability of these effects, inadequate long-term data, missing data, and uncertainties about the dose.

Adalimumab – marketed as Humira by Abbott Laboratories – was first approved in 2002 for treating moderate to severe rheumatoid arthritis in adults, and was approved in 2007 for treating moderate to severe Crohn’s disease. It has also been approved for psoriasis, ankylosing spondylitis, and juvenile idiopathic arthritis indications.

The recommended dosing schedule for UC is one 160-mg starting dose, followed by 80 mg on day 15, and then 40 mg every other week starting at day 29, continuing treatment only in people who have responded within the first 8 weeks.

Abbott filed for approval in January 2011, but the FDA raised questions about whether a higher dose would be more effective and about the strength of the results in the two pivotal trials, including whether the differences in clinical remission rates at 8 and 52 weeks between placebo and treatment were clinically meaningful. The company resubmitted the application for approval, with a slightly different proposed indication: reducing the signs and symptoms, and achieving (instead of inducing and maintaining induction of) clinical remission in adults with moderately to severely active UC, who have had an inadequate response to conventional therapy.

The two double-blind, placebo-controlled, phase III studies compared adalimumab against placebo in 1,094 treatment-refractory patients with moderately to severely active UC with a total Mayo score of 6 to 12 points, and an endoscopy sub-score of 2 or 3, despite current or previous steroid and/or immunosuppressant therapy. In one 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference that was significant.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab (40%), the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference that was statistically significant. At 52 weeks, the remission rate was 17.3% among those on adalimumab, vs. 8.5% among those on placebo, an 8.8% difference that also was statistically significant.

In different votes, the panel nearly unanimously agreed that the 8 week and 52 week clinical remission rates in the studies represented "clinically meaningful benefits."

However, in the second study, 8.5% of the patients on adalimumab were in clinical remission at both weeks 8 and 52, vs. 4.1% among those on placebo. The panel was less unanimous about whether the 4.4% difference between the two groups represented a clinically meaningful benefit of treatment, voting 10-6 with 1 abstention on this question.

Other findings in the 52-week study included a higher steroid discontinuation rate among those on adalimumab, a secondary endpoint: About 13% of those on adalimumab were able to go off steroid treatment before the 52nd week of treatment and had achieved a clinical remission, compared with 5.7% of those on placebo, a statistically significant difference. In addition, the patients on azathioprine or 6-MP at baseline in this study did not appear to benefit from adalimumab: In this subgroup, the remission rate at week 8 among those on adalimumab (12.9%) was similar to the rate among those on placebo (15%). But for those who were not on the immunomodulatory drugs at baseline, the remission rate was nearly 19% among those on adalimumab vs. 6.6% of those on placebo, the FDA reviewer pointed out. In the studies, the safety profile of adalimumab was similar to the placebo, other than a higher rate of injection site reactions among those on adalimumab, and no new safety signals for adalimumab were identified in the trials, according to Abbott.

If the FDA grants approval, adalimumab will be the only self-administered biologic therapy available for patients with UC, the company pointed out. In April 2012, adalimumab was approved in the European Union for treating adults with moderately to severely active UC who have had an inadequate response to conventional therapy, based on the same data submitted to the FDA for the UC indication, according to Abbott.

The company is planning an international registry of patients with UC treated with adalimumab in typical clinical settings to collect long-term safety data, which will include patients in the EU, and, if approved, in the United States. The FDA usually follows the recommendations of its advisory panels, which are not binding. The company expects a decision on approval by the end of the year, according to an Abbott spokesperson.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The approval of a second anti-tumor necrosis factor treatment option for ulcerative colitis is likely, now that the majority of a Food and Drug Administration advisory panel has recommended approval of adalimumab for treating people with moderately to severely active disease.

At a meeting on Aug. 28, the FDA’s Gastrointestinal Drugs Advisory Committee voted 15-2 that the expected benefits of adalimumab – a subcutaneously administered tumor necrosis factor (TNF) blocker – outweighed its potential risks as a treatment for patients with moderately to severely active ulcerative colitis (UC) who have not had an adequate response with conventional treatments. The panel’s recommendation for approval was based on the results of two studies comparing adalimumab against placebo in such patients. But their support for approval came with caveats. While most of the panel agreed that the dose used in the studies had been shown to be clinically effective, they agreed that the optimal dose for treating UC had not yet been determined and that post-approval studies were needed to address dosing, subpopulations of patients who may benefit most from treatment, and long-term safety.

Panel members voting in favor of approval cited the need for more treatments and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects. And although the differences in clinical remission rates between placebo and treatment at 8 weeks and at 1 year were less than 10% – one of the main issues raised by FDA reviewers – most of the panel members said that these differences still represented a clinically meaningful benefit. Infliximab (Remicade), an intravenous TNF blocker, is approved for treating UC and Crohn’s disease in pediatric and adult patients.

Like other panelists, Dr. Andelka LoSavio of the department of gastroenterology and nutrition, Loyola University, Maywood, Ill., said that the outstanding issues should not hold up approval of adalimumab for UC. "Once the drug is on the marketplace, we will have more insight into subpopulations where the drug may be more effective," which was the case with Crohn’s disease and adalimumab.

Although the remission rates in the studies were low, these are difficult-to-treat patients, and the responses were statistically significant, with evidence of a steroid-sparing effect, said panelist Dr. Marc Wishingrad, a gastroenterologist who practices in Santa Monica, Calif. "So it seems to me in a global sense that there is enough benefit here, that overall I would recommend that this drug be approved for this indication," he added.

Panelists supported the manufacturer’s recommendation that if a patient does not respond after 8 weeks of treatment, that treatment should be stopped.

The two statisticians on the panel did not support approval, voting no on the risk-benefit question for reasons that included the modest effects on clinical remission rates, uncertain durability of these effects, inadequate long-term data, missing data, and uncertainties about the dose.

Adalimumab – marketed as Humira by Abbott Laboratories – was first approved in 2002 for treating moderate to severe rheumatoid arthritis in adults, and was approved in 2007 for treating moderate to severe Crohn’s disease. It has also been approved for psoriasis, ankylosing spondylitis, and juvenile idiopathic arthritis indications.

The recommended dosing schedule for UC is one 160-mg starting dose, followed by 80 mg on day 15, and then 40 mg every other week starting at day 29, continuing treatment only in people who have responded within the first 8 weeks.

Abbott filed for approval in January 2011, but the FDA raised questions about whether a higher dose would be more effective and about the strength of the results in the two pivotal trials, including whether the differences in clinical remission rates at 8 and 52 weeks between placebo and treatment were clinically meaningful. The company resubmitted the application for approval, with a slightly different proposed indication: reducing the signs and symptoms, and achieving (instead of inducing and maintaining induction of) clinical remission in adults with moderately to severely active UC, who have had an inadequate response to conventional therapy.

The two double-blind, placebo-controlled, phase III studies compared adalimumab against placebo in 1,094 treatment-refractory patients with moderately to severely active UC with a total Mayo score of 6 to 12 points, and an endoscopy sub-score of 2 or 3, despite current or previous steroid and/or immunosuppressant therapy. In one 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference that was significant.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab (40%), the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference that was statistically significant. At 52 weeks, the remission rate was 17.3% among those on adalimumab, vs. 8.5% among those on placebo, an 8.8% difference that also was statistically significant.

In different votes, the panel nearly unanimously agreed that the 8 week and 52 week clinical remission rates in the studies represented "clinically meaningful benefits."

However, in the second study, 8.5% of the patients on adalimumab were in clinical remission at both weeks 8 and 52, vs. 4.1% among those on placebo. The panel was less unanimous about whether the 4.4% difference between the two groups represented a clinically meaningful benefit of treatment, voting 10-6 with 1 abstention on this question.

Other findings in the 52-week study included a higher steroid discontinuation rate among those on adalimumab, a secondary endpoint: About 13% of those on adalimumab were able to go off steroid treatment before the 52nd week of treatment and had achieved a clinical remission, compared with 5.7% of those on placebo, a statistically significant difference. In addition, the patients on azathioprine or 6-MP at baseline in this study did not appear to benefit from adalimumab: In this subgroup, the remission rate at week 8 among those on adalimumab (12.9%) was similar to the rate among those on placebo (15%). But for those who were not on the immunomodulatory drugs at baseline, the remission rate was nearly 19% among those on adalimumab vs. 6.6% of those on placebo, the FDA reviewer pointed out. In the studies, the safety profile of adalimumab was similar to the placebo, other than a higher rate of injection site reactions among those on adalimumab, and no new safety signals for adalimumab were identified in the trials, according to Abbott.

If the FDA grants approval, adalimumab will be the only self-administered biologic therapy available for patients with UC, the company pointed out. In April 2012, adalimumab was approved in the European Union for treating adults with moderately to severely active UC who have had an inadequate response to conventional therapy, based on the same data submitted to the FDA for the UC indication, according to Abbott.

The company is planning an international registry of patients with UC treated with adalimumab in typical clinical settings to collect long-term safety data, which will include patients in the EU, and, if approved, in the United States. The FDA usually follows the recommendations of its advisory panels, which are not binding. The company expects a decision on approval by the end of the year, according to an Abbott spokesperson.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The approval of a second anti-tumor necrosis factor treatment option for ulcerative colitis is likely, now that the majority of a Food and Drug Administration advisory panel has recommended approval of adalimumab for treating people with moderately to severely active disease.

At a meeting on Aug. 28, the FDA’s Gastrointestinal Drugs Advisory Committee voted 15-2 that the expected benefits of adalimumab – a subcutaneously administered tumor necrosis factor (TNF) blocker – outweighed its potential risks as a treatment for patients with moderately to severely active ulcerative colitis (UC) who have not had an adequate response with conventional treatments. The panel’s recommendation for approval was based on the results of two studies comparing adalimumab against placebo in such patients. But their support for approval came with caveats. While most of the panel agreed that the dose used in the studies had been shown to be clinically effective, they agreed that the optimal dose for treating UC had not yet been determined and that post-approval studies were needed to address dosing, subpopulations of patients who may benefit most from treatment, and long-term safety.

Panel members voting in favor of approval cited the need for more treatments and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects. And although the differences in clinical remission rates between placebo and treatment at 8 weeks and at 1 year were less than 10% – one of the main issues raised by FDA reviewers – most of the panel members said that these differences still represented a clinically meaningful benefit. Infliximab (Remicade), an intravenous TNF blocker, is approved for treating UC and Crohn’s disease in pediatric and adult patients.

Like other panelists, Dr. Andelka LoSavio of the department of gastroenterology and nutrition, Loyola University, Maywood, Ill., said that the outstanding issues should not hold up approval of adalimumab for UC. "Once the drug is on the marketplace, we will have more insight into subpopulations where the drug may be more effective," which was the case with Crohn’s disease and adalimumab.

Although the remission rates in the studies were low, these are difficult-to-treat patients, and the responses were statistically significant, with evidence of a steroid-sparing effect, said panelist Dr. Marc Wishingrad, a gastroenterologist who practices in Santa Monica, Calif. "So it seems to me in a global sense that there is enough benefit here, that overall I would recommend that this drug be approved for this indication," he added.

Panelists supported the manufacturer’s recommendation that if a patient does not respond after 8 weeks of treatment, that treatment should be stopped.

The two statisticians on the panel did not support approval, voting no on the risk-benefit question for reasons that included the modest effects on clinical remission rates, uncertain durability of these effects, inadequate long-term data, missing data, and uncertainties about the dose.

Adalimumab – marketed as Humira by Abbott Laboratories – was first approved in 2002 for treating moderate to severe rheumatoid arthritis in adults, and was approved in 2007 for treating moderate to severe Crohn’s disease. It has also been approved for psoriasis, ankylosing spondylitis, and juvenile idiopathic arthritis indications.

The recommended dosing schedule for UC is one 160-mg starting dose, followed by 80 mg on day 15, and then 40 mg every other week starting at day 29, continuing treatment only in people who have responded within the first 8 weeks.

Abbott filed for approval in January 2011, but the FDA raised questions about whether a higher dose would be more effective and about the strength of the results in the two pivotal trials, including whether the differences in clinical remission rates at 8 and 52 weeks between placebo and treatment were clinically meaningful. The company resubmitted the application for approval, with a slightly different proposed indication: reducing the signs and symptoms, and achieving (instead of inducing and maintaining induction of) clinical remission in adults with moderately to severely active UC, who have had an inadequate response to conventional therapy.

The two double-blind, placebo-controlled, phase III studies compared adalimumab against placebo in 1,094 treatment-refractory patients with moderately to severely active UC with a total Mayo score of 6 to 12 points, and an endoscopy sub-score of 2 or 3, despite current or previous steroid and/or immunosuppressant therapy. In one 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference that was significant.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab (40%), the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference that was statistically significant. At 52 weeks, the remission rate was 17.3% among those on adalimumab, vs. 8.5% among those on placebo, an 8.8% difference that also was statistically significant.

In different votes, the panel nearly unanimously agreed that the 8 week and 52 week clinical remission rates in the studies represented "clinically meaningful benefits."

However, in the second study, 8.5% of the patients on adalimumab were in clinical remission at both weeks 8 and 52, vs. 4.1% among those on placebo. The panel was less unanimous about whether the 4.4% difference between the two groups represented a clinically meaningful benefit of treatment, voting 10-6 with 1 abstention on this question.

Other findings in the 52-week study included a higher steroid discontinuation rate among those on adalimumab, a secondary endpoint: About 13% of those on adalimumab were able to go off steroid treatment before the 52nd week of treatment and had achieved a clinical remission, compared with 5.7% of those on placebo, a statistically significant difference. In addition, the patients on azathioprine or 6-MP at baseline in this study did not appear to benefit from adalimumab: In this subgroup, the remission rate at week 8 among those on adalimumab (12.9%) was similar to the rate among those on placebo (15%). But for those who were not on the immunomodulatory drugs at baseline, the remission rate was nearly 19% among those on adalimumab vs. 6.6% of those on placebo, the FDA reviewer pointed out. In the studies, the safety profile of adalimumab was similar to the placebo, other than a higher rate of injection site reactions among those on adalimumab, and no new safety signals for adalimumab were identified in the trials, according to Abbott.

If the FDA grants approval, adalimumab will be the only self-administered biologic therapy available for patients with UC, the company pointed out. In April 2012, adalimumab was approved in the European Union for treating adults with moderately to severely active UC who have had an inadequate response to conventional therapy, based on the same data submitted to the FDA for the UC indication, according to Abbott.

The company is planning an international registry of patients with UC treated with adalimumab in typical clinical settings to collect long-term safety data, which will include patients in the EU, and, if approved, in the United States. The FDA usually follows the recommendations of its advisory panels, which are not binding. The company expects a decision on approval by the end of the year, according to an Abbott spokesperson.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.